Methamphetamine (MA) abuse and dependence are major public health concerns;however, a widely accepted pharmacotherapy has not yet been identified (Elkashef, 2008). Efforts in this regard have been limited, in part, by the inadequate sensitivity of human laboratory methods for measuring abuse-related behavioral effects (e.g., reinforcing effects) of MA. Enhancing the sensitivity of the human laboratory procedures to reveal sizable reinforcing effects could facilitate the testing of pharmacological agents in modifying these effects. Only a handful of studies have measured the reinforcing effects of MA in the human laboratory, and the procedures used (e.g., choosing between drug and monetary rewards) have yielded only small to moderate effects. The modest reinforcing effects of MA found in these procedures limit the extent to which pharmacological modification can be examined. Notably, progressive-ratio procedure is an efficient method for assessing the reinforcing effects of abused drug. In this procedure, the response requirement (i.e., ratio) for obtaining each reinforcer progressively increases until subjects stop responding. The final ratio completed is the "break point," which reflects the maximum effort expended to receive the reinforcer. Progressive-ratio procedures have not yet been used to study human MA self-administration;and, although d-amphetamine self-administration has been examined using this procedure, the modest effects observed have limited its utility for evaluating pharmacotherapies for amphetamine abuse. Particular experimental design parameters likely contributed to the modest effects found in the d- amphetamine progressive-ratio studies. Notably, in these studies response requirements ranged from either 50 to 6,400 or 25 to 3,200 responses (i.e., mouse clicks) to earn capsules. This contributed to high responses for placebo and low responses for d-amphetamine, resulting in small to moderate magnitudes of the measured reinforcement. We propose to use different response requirements (i.e., 400 to 1,800 clicks) under a progressive-ratio schedule. We hypothesize that the higher "minimal" and lower "maximal" ratios would decrease responding for placebo and increase responding for MA, revealing an enhanced magnitude of the reinforcing effects of MA. Ten MA-dependent individuals will participate in this 11-day inpatient study. They will first sample IV doses of MA (0, 8, 16, and 24 mg), and in subsequent sessions, they will receive opportunities to work for the sampled dose on a progressive-ratio procedure. A battery of subjective-effect questionnaires and cardiovascular measures will be assessed to characterize the effects of MA. We expect that the proposed response requirements will result in low levels of placebo taking and a wide difference between the number of placebo and MA infusions earned, resulting in a large effect size of the MA reinforcement. The proposed research offers to provide a sensitive human laboratory procedure for assessing reinforcing effects of MA. The outcomes could help develop an efficient and economical human laboratory screen of medications for MA dependence. PUBLIC HEALTH RELEVANCE: The application offers to refine a human laboratory procedure, the progressive-ratio schedule, for assessing reinforcing effects of MA in MA-dependent individuals. A widely accepted medication for treating MA dependence is not yet available, and the cost associated with clinical trials is substantial. An efficient human laboratory procedure can, therefore, provide an economical approach for determining preliminary efficacy of medications for MA dependence.